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PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration

Neuropsychopharmacology volume 48, pages 1436–1445 (2023)Cite this article

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Abstract

Brain imaging studies using positron emission tomography (PET) have shown that long-term cocaine use is associated with lower levels of dopamine (DA) D2/D3 receptors (D2/D3R); less consistent are the effects on DA transporter (DAT) availability. However, most studies have been conducted in male subjects (humans, monkeys, rodents). In this study, we used PET imaging in nine drug-naïve female cynomolgus monkeys to determine if baseline measures of DAT, with [18F]FECNT, and D2/D3R availability, with [11C]raclopride, in the caudate nucleus, putamen and ventral striatum were associated with rates of cocaine self-administration and if these measures changed during long-term (~13 months) cocaine self-administration and following time-off (3–9 months) from cocaine. Cocaine (0.2 mg/kg/injection) and 1.0 g food pellets were available under a multiple fixed-interval (FI) 3-min schedule of reinforcement. In contrast to what has been observed in male monkeys, baseline D2/D3R availability was positively correlated with rates of cocaine self-administration only during the first week of exposure; DAT availability did not correlate with cocaine self-administration. D2/D3R availability decreased ~20% following cumulative intakes of 100 and 1000 mg/kg cocaine; DAT availability did not significantly change. These reductions in D2/D3R availability did not recover over 9 months of time-off from cocaine. To determine if these reductions were reversible, three monkeys were implanted with osmotic pumps that delivered raclopride for 30 days. We found that chronic treatment with the D2/D3R antagonist raclopride increased D2/D3R availability in the ventral striatum but not in the other regions when compared to baseline levels. Over 13 months of self-administration, tolerance did not develop to the rate-decreasing effects of self-administered cocaine on food-reinforced responding, but number of injections and cocaine intake significantly increased over the 13 months. These data extend previous findings to female monkeys and suggest sex differences in the relationship between D2/D3R availability related to vulnerability and long-term cocaine use.

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Fig. 1: Changes in [11C]raclopride (left panels) and [18F]FECNT (right panels) DVRs as a function of cocaine intake.
Fig. 2: Effects of cocaine self-administration on food- and cocaine-maintained responding.
Fig. 3: Changes in [11C]raclopride as a function of time-off from cocaine self-administration.
Fig. 4: Changes in [11C]raclopride as a function of cocaine intake, time-off from cocaine abstinence, and 30-days chronic treatment with raclopride.

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Acknowledgements

We would like to thank Michael Rowe, Michelle Bell, Lorne Kerley and Stephanie Rideout for excellent technical assistance and Dr. Leonard Howell for coordinating the [18F]FECNT PET studies. This research was supported by the National Institute on Drug Abuse Grant DA017763.

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Authors and Affiliations

  1. Department of Physiology & Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Mia I. Allen, Angela N. Duke, Susan H. Nader, Adrienne Adler-Neal & Michael A. Nader

  2. Department of Radiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Kiran K. Solingapuram Sai, H. Donald Gage, Akiva Mintz & Michael A. Nader

  3. Department of Biostatistics, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA

    Beth A. Reboussin

  4. Department of Radiology, Emory University School of Medicine, 1515 Dickey Drive, Atlanta, GA, 30322, USA

    Ronald J. Voll & Mark M. Goodman

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Contributions

MAN designed the experiments. AND, AA-N and SHN performed the behavioral studies, including intravenous catheterization. AND and SHN analyzed the PET data, HDG provided technical guidance with initial PET analyses, KKSS, RJV, AM and MMG were involved in the synthesis of both radiotracers and BAR and MIA were responsible for the statistical analyses. The manuscript was written by MIA and MAN. All authors read a draft of this manuscript and provided critical edits to the content.

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Correspondence to Michael A. Nader.

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Allen, M.I., Duke, A.N., Nader, S.H. et al. PET imaging of dopamine transporters and D2/D3 receptors in female monkeys: effects of chronic cocaine self-administration. Neuropsychopharmacol. 48, 1436–1445 (2023). https://doi.org/10.1038/s41386-023-01622-3

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